Global mapping of CARM1 substrates defines enzyme specificity and substrate recognition

Evgenia Shishkova, Hao Zeng, Fabao Liu, Nicholas W. Kwiecien, Alexander S. Hebert, Joshua J. Coon and Wei Xu ()
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Evgenia Shishkova: University of Wisconsin – Madison
Hao Zeng: McArdle Laboratory for Cancer Research, University of Wisconsin – Madison
Fabao Liu: McArdle Laboratory for Cancer Research, University of Wisconsin – Madison
Nicholas W. Kwiecien: The Genome Center of Wisconsin, University of Wisconsin – Madison
Alexander S. Hebert: The Genome Center of Wisconsin, University of Wisconsin – Madison
Joshua J. Coon: University of Wisconsin – Madison
Wei Xu: McArdle Laboratory for Cancer Research, University of Wisconsin – Madison

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Protein arginine methyltransferases (PRMTs) introduce arginine methylation, a post-translational modification with the increasingly eminent role in normal physiology and disease. PRMT4 or coactivator-associated arginine methyltransferase 1 (CARM1) is a propitious target for cancer therapy; however, few CARM1 substrates are known, and its mechanism of substrate recognition is poorly understood. Here we employed a quantitative mass spectrometry approach to globally profile CARM1 substrates in breast cancer cell lines. We identified >130 CARM1 protein substrates and validated in vitro >90% of sites they encompass. Bioinformatics analyses reveal enrichment of proline-containing motifs, in which both methylation sites and their proximal sequences are frequently targeted by somatic mutations in cancer. Finally, we demonstrate that the N-terminus of CARM1 is involved in substrate recognition and nearly indispensable for substrate methylation. We propose that development of CARM1-specific inhibitors should focus on its N-terminus and predict that other PRMTs may employ similar mechanism for substrate recognition.

Date: 2017
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DOI: 10.1038/ncomms15571

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